title: Specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukemia.
abstract: Children with Down syndrome (DS) have a greatly increased risk of acute megakaryoblastic leukemia (AMKL) and acute lymphoblastic leukemia (ALL). Both DS-AMKL and the related transient myeloproliferative disorder (TMD) have GATA1 mutations as obligatory, early events. To identify mutations contributing to leukemogenesis in DS-ALL, we undertook sequencing of candidate genes, including FLT3, RAS, PTPN11, BRAF, and JAK2. Sequencing of the JAK2 pseudokinase domain identified a specific, acquired mutation, JAK2R683, in 12 (28%) of 42 DS-ALL cases. Functional studies of the common JAK2R683G mutation in murine Ba/F3 cells showed growth factor independence and constitutive activation of the JAK/STAT signaling pathway. High-resolution SNP array analysis of 9 DS-ALL cases identified additional submicroscopic deletions in key genes, including ETV6, CDKN2A, and PAX5. These results infer a complex molecular pathogenesis for DS-ALL leukemogenesis, with trisomy 21 as an initiating or first hit and with chromosome aneuploidy, gene deletions, and activating JAK2 mutations as complementary genetic events.
authors.affiliation: Section of Haemato-Oncology, The Institute of Cancer Research, Sutton, United Kingdom. lyndal.kearney@icr.ac.uk
authors.forename: Lyndal
authors.initials: L
authors.lastname: Kearney
authors.forename: David
authors.initials: D
authors.lastname: Gonzalez De Castro
authors.forename: Jenny
authors.initials: J
authors.lastname: Yeung
authors.forename: Julia
authors.initials: J
authors.lastname: Procter
authors.forename: Sharon W
authors.initials: SW
authors.lastname: Horsley
authors.forename: Minenori
authors.initials: M
authors.lastname: Eguchi-Ishimae
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Bateman
authors.forename: Kristina
authors.initials: K
authors.lastname: Anderson
authors.forename: Tracy
authors.initials: T
authors.lastname: Chaplin
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Young
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Harrison
authors.forename: Helena
authors.initials: H
authors.lastname: Kempski
authors.forename: Chi Wai E
authors.initials: CW
authors.lastname: So
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Ford
authors.forename: Mel
authors.initials: M
authors.lastname: Greaves
mesh_terms: D000818:Animals; D001483:Base Sequence; D004252:DNA Mutational Analysis; D004314:Down Syndrome / Q000150:complications / Q000235:genetics*; D017353:Gene Deletion; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D051379:Mice; D009154:Mutation; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*
chemical_list: D053614:Janus Kinase 2